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Phytoestrogens inhibit growth and MAP kinase activity in human aortic smooth muscle cells
R K Dubey1, D G Gillespie, B Imthurn
1Center for Clinical Pharmacology, Department of Medicine , University of Pittsburgh Medical Center, PA 15213-2582, USA. rag@fhk.smtp.usz.ch
Abstract:
-Estrogens are known to induce cardioprotective effects by inhibiting smooth muscle cell (SMC) growth and neointima formation. However, the use of estrogens as cardioprotective agents is limited by carcinogenic effects in women and feminizing effects in men. If noncarcinogenic and nonfeminizing estrogenlike compounds, such as natural phytoestrogens, afford cardioprotection, this would provide a safe method for prevention of cardiovascular disease in both men and women. Therefore, we evaluated and compared in human aortic SMCs the effects of phytoestrogens (formononetin, genistein, biochanin A, daidzein, and equol) on 2.5% fetal calf serum-induced proliferation (3H-thymidine incorporation and cell number), collagen synthesis (3H-proline incorporation), and total protein synthesis (3H-leucine incorporation) and on PDGF-BB (25 ng/mL)-induced migration (modified Boydens chambers). Moreover, the effects of phytoestrogens on PDGF-BB (25 ng/mL)-induced mitogen-activated protein kinase (MAP kinase) activity in SMCs was also studied. Phytoestrogens inhibited proliferation, collagen and total protein synthesis, migration, and MAP kinase activity in a concentration-dependent manner and in the following order of potency: biochanin A>genistein>equol>daidzein>formononetin. In conclusion, our studies provide the first evidence that in human aortic SMCs phytoestrogens inhibit mitogen-induced proliferation, migration and extracellular matrix synthesis and inhibit/downregulate MAP kinase activity. Thus, phytoestrogens may confer protective effects on the cardiovascular system by inhibiting vascular remodeling and neointima formation and may be clinically useful as a safer substitute for feminizing estrogens in preventing cardiovascular disease in both women and men.
Insights
Phytoestrogens, like biochanin A and genistein, safely inhibit vascular smooth muscle cell growth and migration. These compounds may prevent cardiovascular disease by offering cardioprotection without estrogenic side effects.
Area of Science:
- Cardiovascular Science
- Endocrinology
- Molecular Biology
Background:
- Estrogens offer cardioprotection by inhibiting smooth muscle cell (SMC) proliferation and neointima formation.
- Estrogen use is limited by carcinogenic and feminizing side effects.
- Phytoestrogens, natural estrogen-like compounds, may offer a safer alternative.
Purpose of the Study:
- To evaluate and compare the cardioprotective effects of various phytoestrogens in human aortic SMCs.
- To investigate the impact of phytoestrogens on SMC proliferation, collagen synthesis, protein synthesis, migration, and MAP kinase activity.
Main Methods:
- Human aortic SMCs were treated with phytoestrogens (formononetin, genistein, biochanin A, daidzein, equol).
- Assessed proliferation (3H-thymidine incorporation, cell number), collagen synthesis (3H-proline incorporation), and protein synthesis (3H-leucine incorporation).
- Evaluated PDGF-BB-induced migration and MAP kinase activity.
Main Results:
- Phytoestrogens inhibited SMC proliferation, collagen and total protein synthesis, migration, and MAP kinase activity in a concentration-dependent manner.
- The order of potency was biochanin A > genistein > equol > daidzein > formononetin.
- Phytoestrogens demonstrated significant inhibition of mitogen-induced vascular remodeling and extracellular matrix synthesis.
Conclusions:
- Phytoestrogens inhibit proliferation, migration, and extracellular matrix synthesis in human aortic SMCs.
- Phytoestrogens downregulate MAP kinase activity, a key signaling pathway in vascular remodeling.
- Phytoestrogens represent a potentially safer therapeutic strategy for preventing cardiovascular disease compared to traditional estrogens.